KEAP1 inhibition is neuroprotective and suppresses the development of epilepsy

Tawfeeq Shekh-Ahmad, Ramona Eckel, Sharadha Dayalan Naidu, Maureen Higgins, Masayuki Yamamoto, Albena Dinkova-Kostova, Stjepana Kovac, Andrey Y. Abramov (Lead / Corresponding author), Matthew C. Walker (Lead / Corresponding author)

    Research output: Contribution to journalArticle

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    Abstract

    Hippocampal sclerosis is a common acquired disease that is a major cause of drug-resistant epilepsy. A mechanism that has been proposed to lead from brain insult to hippocampal sclerosis is the excessive generation of reactive oxygen species, and consequent mitochondrial failure. Here we use a novel strategy to increase endogenous antioxidant defences using RTA 408, which we show activates nuclear factor erythroid 2-related factor 2 (Nrf2, encoded by NFE2L2) through inhibition of kelch like ECH associated protein 1 (KEAP1) through its primary sensor C151. Activation of Nrf2 with RTA 408 inhibited reactive oxygen species production, mitochondrial depolarization and cell death in an in vitro model of seizure-like activity. RTA 408 given after status epilepticus in vivo increased ATP, prevented neuronal death, and dramatically reduced (by 94%) the frequency of late spontaneous seizures for at least 4 months following status epilepticus. Thus, acute KEAP1 inhibition following status epilepticus exerts a neuroprotective and disease-modifying effect, supporting the hypothesis that reactive oxygen species generation is a key event in the development of epilepsy.

    Original languageEnglish
    Pages (from-to)1390-1403
    Number of pages14
    JournalBrain
    Volume141
    Issue number5
    Early online date12 Mar 2018
    DOIs
    Publication statusPublished - May 2018

    Fingerprint

    Status Epilepticus
    Epilepsy
    Reactive Oxygen Species
    Sclerosis
    Seizures
    Cell Death
    Antioxidants
    Adenosine Triphosphate
    Brain
    N-(11-cyano-2,2,6a,6b,9,9,12a-heptmethyl-10,14-dioxo-1,3,4,5,6a,6b,7,8,8a,9,10,12a,14,14a,14b-hexadecahydro-2H-picen-4a-yl)-2-2-difluoropropionamide
    Kelch-Like ECH-Associated Protein 1

    Keywords

    • epilepsy
    • epileptogenesis
    • mitochondrial dysfunction
    • Nrf2-KEAP1 pathway
    • oxidative stress

    Cite this

    Shekh-Ahmad, T., Eckel, R., Dayalan Naidu, S., Higgins, M., Yamamoto, M., Dinkova-Kostova, A., ... Walker, M. C. (2018). KEAP1 inhibition is neuroprotective and suppresses the development of epilepsy. Brain, 141(5), 1390-1403. https://doi.org/10.1093/brain/awy071
    Shekh-Ahmad, Tawfeeq ; Eckel, Ramona ; Dayalan Naidu, Sharadha ; Higgins, Maureen ; Yamamoto, Masayuki ; Dinkova-Kostova, Albena ; Kovac, Stjepana ; Abramov, Andrey Y. ; Walker, Matthew C. / KEAP1 inhibition is neuroprotective and suppresses the development of epilepsy. In: Brain. 2018 ; Vol. 141, No. 5. pp. 1390-1403.
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    abstract = "Hippocampal sclerosis is a common acquired disease that is a major cause of drug-resistant epilepsy. A mechanism that has been proposed to lead from brain insult to hippocampal sclerosis is the excessive generation of reactive oxygen species, and consequent mitochondrial failure. Here we use a novel strategy to increase endogenous antioxidant defences using RTA 408, which we show activates nuclear factor erythroid 2-related factor 2 (Nrf2, encoded by NFE2L2) through inhibition of kelch like ECH associated protein 1 (KEAP1) through its primary sensor C151. Activation of Nrf2 with RTA 408 inhibited reactive oxygen species production, mitochondrial depolarization and cell death in an in vitro model of seizure-like activity. RTA 408 given after status epilepticus in vivo increased ATP, prevented neuronal death, and dramatically reduced (by 94{\%}) the frequency of late spontaneous seizures for at least 4 months following status epilepticus. Thus, acute KEAP1 inhibition following status epilepticus exerts a neuroprotective and disease-modifying effect, supporting the hypothesis that reactive oxygen species generation is a key event in the development of epilepsy.",
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    author = "Tawfeeq Shekh-Ahmad and Ramona Eckel and {Dayalan Naidu}, Sharadha and Maureen Higgins and Masayuki Yamamoto and Albena Dinkova-Kostova and Stjepana Kovac and Abramov, {Andrey Y.} and Walker, {Matthew C.}",
    note = "This work was supported by the European Union’s Seventh Framework Programme (FP7/2007- 2013) under grant agreement n°602102 (EPITARGET) and Epilepsy Research UK and the Biotechnology and Biological Sciences Research Council (Project Grant BB/L01923X/1).",
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    Shekh-Ahmad, T, Eckel, R, Dayalan Naidu, S, Higgins, M, Yamamoto, M, Dinkova-Kostova, A, Kovac, S, Abramov, AY & Walker, MC 2018, 'KEAP1 inhibition is neuroprotective and suppresses the development of epilepsy', Brain, vol. 141, no. 5, pp. 1390-1403. https://doi.org/10.1093/brain/awy071

    KEAP1 inhibition is neuroprotective and suppresses the development of epilepsy. / Shekh-Ahmad, Tawfeeq; Eckel, Ramona ; Dayalan Naidu, Sharadha; Higgins, Maureen; Yamamoto, Masayuki; Dinkova-Kostova, Albena; Kovac, Stjepana; Abramov, Andrey Y. (Lead / Corresponding author); Walker, Matthew C. (Lead / Corresponding author).

    In: Brain, Vol. 141, No. 5, 05.2018, p. 1390-1403.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - KEAP1 inhibition is neuroprotective and suppresses the development of epilepsy

    AU - Shekh-Ahmad, Tawfeeq

    AU - Eckel, Ramona

    AU - Dayalan Naidu, Sharadha

    AU - Higgins, Maureen

    AU - Yamamoto, Masayuki

    AU - Dinkova-Kostova, Albena

    AU - Kovac, Stjepana

    AU - Abramov, Andrey Y.

    AU - Walker, Matthew C.

    N1 - This work was supported by the European Union’s Seventh Framework Programme (FP7/2007- 2013) under grant agreement n°602102 (EPITARGET) and Epilepsy Research UK and the Biotechnology and Biological Sciences Research Council (Project Grant BB/L01923X/1).

    PY - 2018/5

    Y1 - 2018/5

    N2 - Hippocampal sclerosis is a common acquired disease that is a major cause of drug-resistant epilepsy. A mechanism that has been proposed to lead from brain insult to hippocampal sclerosis is the excessive generation of reactive oxygen species, and consequent mitochondrial failure. Here we use a novel strategy to increase endogenous antioxidant defences using RTA 408, which we show activates nuclear factor erythroid 2-related factor 2 (Nrf2, encoded by NFE2L2) through inhibition of kelch like ECH associated protein 1 (KEAP1) through its primary sensor C151. Activation of Nrf2 with RTA 408 inhibited reactive oxygen species production, mitochondrial depolarization and cell death in an in vitro model of seizure-like activity. RTA 408 given after status epilepticus in vivo increased ATP, prevented neuronal death, and dramatically reduced (by 94%) the frequency of late spontaneous seizures for at least 4 months following status epilepticus. Thus, acute KEAP1 inhibition following status epilepticus exerts a neuroprotective and disease-modifying effect, supporting the hypothesis that reactive oxygen species generation is a key event in the development of epilepsy.

    AB - Hippocampal sclerosis is a common acquired disease that is a major cause of drug-resistant epilepsy. A mechanism that has been proposed to lead from brain insult to hippocampal sclerosis is the excessive generation of reactive oxygen species, and consequent mitochondrial failure. Here we use a novel strategy to increase endogenous antioxidant defences using RTA 408, which we show activates nuclear factor erythroid 2-related factor 2 (Nrf2, encoded by NFE2L2) through inhibition of kelch like ECH associated protein 1 (KEAP1) through its primary sensor C151. Activation of Nrf2 with RTA 408 inhibited reactive oxygen species production, mitochondrial depolarization and cell death in an in vitro model of seizure-like activity. RTA 408 given after status epilepticus in vivo increased ATP, prevented neuronal death, and dramatically reduced (by 94%) the frequency of late spontaneous seizures for at least 4 months following status epilepticus. Thus, acute KEAP1 inhibition following status epilepticus exerts a neuroprotective and disease-modifying effect, supporting the hypothesis that reactive oxygen species generation is a key event in the development of epilepsy.

    KW - epilepsy

    KW - epileptogenesis

    KW - mitochondrial dysfunction

    KW - Nrf2-KEAP1 pathway

    KW - oxidative stress

    UR - http://www.scopus.com/inward/record.url?scp=85047058349&partnerID=8YFLogxK

    U2 - 10.1093/brain/awy071

    DO - 10.1093/brain/awy071

    M3 - Article

    VL - 141

    SP - 1390

    EP - 1403

    JO - Brain

    JF - Brain

    SN - 0006-8950

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    Shekh-Ahmad T, Eckel R, Dayalan Naidu S, Higgins M, Yamamoto M, Dinkova-Kostova A et al. KEAP1 inhibition is neuroprotective and suppresses the development of epilepsy. Brain. 2018 May;141(5):1390-1403. https://doi.org/10.1093/brain/awy071